The present invention concerns tricyclic xcex943-piperidines having central xcex12-adrenoceptor antagonist activity. It further relates to their preparation, compositions comprising them and their use as a medicine.
Central xcex12-adrenoceptor antagonists are known to increase noradrenaline release by blocking presynaptic xcex12-receptors which exert an inhibiting control over the release of the neurotransmitter. By increasing the noradrenaline concentrations, xcex12-antagonists can be used clinically for the treatment or prophylaxis of depression, cognitive disturbances, Parkinson""s disease, diabetes mellitus, sexual dysfunction and impotence, elevated intraocular pressure, and diseases related to disturbed enterokinesia, since all these conditions are associated with a deficiency of noradrenaline in the central or peripheral nervous system.
The compounds of the present invention are novel and have a specific and selective binding affinity for the different known subtypes of the xcex12-adrenoceptors, i.e. the xcex12A, xcex12B and xcex12C-adrenoceptor.
The present invention concerns the compounds of formula 
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
Alk is C1-6alkanediyl;
n is 1 or 2;
X1 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(xe2x95x90O)xe2x80x94 or xe2x80x94S(xe2x95x90O)2xe2x80x94;
each R1 is independently hydrogen, halogen, C1-6alkyl, nitro, hydroxy or
C1-4alkyloxy;
D is a radical of formula 
wherein
each m independently is 0, 1 or 2;
X2 is xe2x80x94Oxe2x80x94 or xe2x80x94NR11xe2x80x94;
each X3 independently is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR11xe2x80x94;
X4 is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CH2xe2x80x94Sxe2x80x94 or xe2x80x94NR12xe2x80x94;
X5 and X6 each independently are xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR11xe2x80x94;
R2 is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl;
R3 is hydrogen, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino or mono- or di(C1-6alkyl)amino;
R4, R5, R6, R7, R8, R9, R10, R11 and R15 each independently are hydrogen or C1-6alkyl;
R12 is hydrogen, C1-6alkyl, C1-6alkyloxyC1-6alkyl or pyridinylC1-6alkyl;
R13, R14 sand R16 each independently are halo or C1-6alkyl;
R3 and R4 taken together may form a bivalent radical xe2x80x94R3xe2x80x94R4xe2x80x94 of formula
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-1);
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-2);
xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-3);
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-4) or
xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-5);
wherein one or two hydrogen atoms of said radicals (a-1) to (a-5) each independently may be replaced by halo, C1-6alkyl, arylC1-6alkyl, trifluoromethyl, amino, hydroxy, C1-6alalkyloxy or C1-10alkylcarbonyloxy; or
where possible, two geminal hydrogen atoms may be replaced by C1-6alalkylidene or arylC1-6alkylidene; or
xe2x80x94R3xe2x80x94R4xe2x80x94 may also be
xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-6);
xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-7);
xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-9);
xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-9);
xe2x80x94NHxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94xe2x80x83xe2x80x83(a-10);
xe2x80x94NHxe2x80x94CHxe2x95x90CHxe2x80x94xe2x80x83xe2x80x83(a-11);
xe2x80x94NHxe2x80x94CHxe2x95x90Nxe2x80x94xe2x80x83xe2x80x83(a-12);
xe2x80x94Sxe2x80x94CHxe2x95x90Nxe2x80x94xe2x80x83xe2x80x83(a-13) or
xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94xe2x80x83xe2x80x83(a-14);
wherein one or where possible two or three hydrogen atoms in said radicals (a-6) to (a-14) each independently may be replaced by C1-6alkyl or aryl; and
aryl is phenyl or phenyl substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, trifluoromethyl, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, mercapto, amino, mono- and di(C1-6alkyl)amino, carboxyl, C1-6alkyloxycarbonyl and C1-6alkylcarbonyl.
As used in the foregoing definitions the term halogen is generic to fluoro, chloro, bromo and iodo. The term C1-4alkyl defines straight and branched saturated hydro-carbons, having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl and the like. The term C1-6alkyl is meant to include C1-4alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, hexyl and the like. The term C1-10alkyl is meant to include C1-6alkyl radicals and the higher homologues thereof having 7 to 10 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl and the like. The term C1-5alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 1 to 5 carbon atoms such as, for example, methylene, 1,2-ethane-diyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl and the like. C1-6alkanediyl is meant to include C1-5alkanediyl and the higher homologue thereof havin 6 carbon atoms such as 1,6-hexanediyl and the like. The term C1-6alkylidene defines bivalent straight or branch chained alkylidene radicals having from 1 to 6 carbon atoms such as, for example, methylene, ethylidene, 1-propylidene, 1-butylidene, 1-pentylidene, 1-hexylidene and the like.
The addition salts as mentioned herein are meant to comprise the therapeutically active addition salt forms which the compounds of formula (I) are able to form with appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.
The pharmaceutically acceptable addition salts as mentioned hereinabove are also meant to comprise the therapeutically active non-toxic base, in particular, a metal or amine addition salt forms which the compounds of formula (I) are able to form. Said salts can conveniently be obtained by treating the compounds of formula (I) containing acidic hydrogen atoms with appropriate organic and inorganic bases such as, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely said salt forms can be converted by treatment with an appropriate base or acid into the free acid or base form.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) are able to form and said solvates are meant to be included within the scope of the present invention. Examples of such solvates are, e.g. the hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
The term stereochemically isomeric forms as used herein defines all the possible isomeric forms in which the compounds of formula (I) may occur. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
As used hereinafter, when the position of the R1 substitutent is referred to, the following numbering is used: 
Whenever used hereinafter, the term compounds of formula (I) is meant to include also the N-oxide forms, the pharmaceutically acceptable addition salts and all stereoisomeric forms.
Special compounds are those compounds of formula (I) wherein D is a radical of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k) or (I); m is 0; and aryl is phenyl or phenyl substituted with halo or C1-6alkyl.
An interesting group of compounds are those compounds of formula (I) wherein n is 1 and R1 is hydrogen, chloro, fluoro, methyl, methoxy or nitro, in particular R1 is hydrogen, chloro, fluoro, methyl or methoxy.
In case R1 is other than hydrogen, then R1 is suitably connected to the tricyclic ring system in the 6 or 7 position.
Another interesting group of compounds are those compounds of formula (I) wherein Alk is methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl or 1,5-pentanediyl.
Still another interesting group of compounds are those compounds of formula (I) wherein D is a radical of formula (a) wherein R2 is aryl or methyl and wherein R3 and R4 are taken together to form a bivalent radical of formula (a-5) or (a-8); or D is a radical of formula (b) wherein R5 and R6 are C1-6alkyl, preferably R5 and R6 are methyl; or D is a radical of formula (c) wherein R7 is hydrogen; or D is a radical of formula (d) wherein X2 is xe2x80x94NR11xe2x80x94 and R11 is hydrogen; or D is a radical of formula (e); or D is a radical of formula (f) wherein X3 is xe2x80x94Sxe2x80x94 and R8 is hydrogen or C1-6alkyl, preferably R8 is methyl; or D is a radical of formula (g) wherein X4 is xe2x80x94CH2xe2x80x94Sxe2x80x94 or xe2x80x94NR12xe2x80x94 and R12 is C1-6alkyloxyC1-6alkyl or pyridinylC1-6alkyl, preferable R12 is ethyloxyethyl or pyridinylmethyl; or D is a radical of formula (h) wherein X5 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 and R10 is hydrogen; or D is a radical of formula (); or D is a radical of formula (k) wherein m is preferably 1 and R13 is halo.
Particular compounds are those compounds of formula (I) wherein n is X1 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94.
Preferred compounds are those compounds of formula (I) wherein n is 1, R1 is hydrogen, chloro, fluoro, methoxy or methyl, X1 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 and D is a radical of formula (a), (b), (c), (d), (e), (f), (g), (h), (j) or (k).
More preferred compounds are those compounds of formula (I) wherein D is a radical of formula (a), (c), (d), (f) and (h); X1 is O or S; n is 1; R1 is hydrogen, halo or methyl and is substituted in the 6 position; and Alk is 1,2-ethanediyl, 1,3-propanediyl or 1,4-butanediyl.
Most preferred compounds are the compounds depicted below or their N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof: 
The compounds of formula (I) can generally be prepared by N-alkylating an intermediate of formula (II) with an alkylating reagent of formula (II) following the procedure described in EP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255. In particular, the N-alkylation may be performed in a reaction-inert solvent such as, methyl isobutyl keton, N,N-dimethylformamide or N,N-dimethyl-acetamide, in the presence of a base, for example, triethylamine, sodium carbonate or sodiumbicarbonate, and optionally in the presence of a catalyst such as potassium iodide. 
In intermediate (III), W1 represents an appropriate reactive leaving group such as, halo, e.g. chloro, bromo or iodo; sulfonyloxy, e.g. methanesulfonyloxy, 4-methyl-benzenesulfonyloxy.
In this and the following reactions, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as extraction, crystallization, trituration and chromatography.
The compounds of formula (I) wherein D is a radical of formula (f), being represented by formula (I-f), can be prepared by N-alkylating an amine of formula (IV) with an intermediate of formula (V) wherein W2 is an appropriate reactive leaving group such as, for example, a halogen. 
A specific way of preparing the compounds of formula (I) wherein D is a radical of formula (j) and Alk is xe2x80x94(Alkxe2x80x2)pxe2x80x94CH2xe2x80x94 wherein Alkxe2x80x2 is C1-5alkanediyl and p is 0 or 1, said compounds being represented by formula (I-j), involves the reductive N-alkylation of an intermediate of formula (II) with an aldehyde derivative of formula (VI). 
Said reductive N-alkylation reaction may conveniently be carried out by reducing a mixture of the reactants in a suitable reaction-inert solvent following art-known reductive N-alkylation procedures. In particular, the reaction mixture maybe stirred and/or heated in order to enhance the reaction rate. Suitable solvents are, for example, water; methanol, ethanol, 2-propanol and the like. The reaction is conveniently carried out either with sodium cyanoborohydride, sodium borohydride, formic acid or a salt thereof and the like reducing agents, or alternatively under hydrogen atmosphere, optionally at an increased temperature and/or pressure, in the presence of an appropriate catalyst such as, for example, palladium-on-charcoal, platinum-on-charcoal and the like. In order to prevent the undesired further hydrogenation of certain functional groups in the reactants and the reaction products, it may be advantageous to add an appropriate catalyst-poison to the reaction mixture, e.g., thiophene, quinoline-sulphur and the like. In some instances it may also be advantageous to add an alkali metal salt to the reaction mixture such as, for example, potassium fluoride, potassium acetate and the like salts.
The compounds of formula (I) may be converted into each other following art-known functional group transformation reactions.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substtituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
A number of intermediates and starting materials are commercially available or are known compounds which may be prepared according to art-known methodologies.
For example, some of the intermediates of formula (III) and their preparations are described in EP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255.
Intermediates of formula (II) wherein X1 is xe2x80x94Oxe2x80x94 can be prepared as described in Syn. Comm. (1995), p3883-3900 and J. Chem. Soc., 1965, p4939-4953 and using methods known in the art. A general procedure is depicted in scheme 1. 
Intermediates of formula (II) wherein X1 is xe2x80x94Sxe2x80x94 can be prepared according to J. Med. Chem., 1992, 35(7), p1176-1182 and using methods known in the art. A general procedure is depicted in scheme 2. 
Alternatively, intermediates of formula (II) can be prepared according to Synth. Comm., 1995, p3883-3900 and using methods known in the art. A general procedure is depicted in scheme 3. 
Intermediates of formula (III) wherein D is a radical of formula (h), said intermediates being represented by formula (III-h), can be prepared by reacting a benzisoxazole or benzisothiazole of formula (VI) wherein W3 is a suitable leaving group such as, a halogen, with an amino-alcohol derivative of formula (VIII) in the presence of a catalyst such as, potassium iodide. Conveniently, the reaction mixture is stirred at elevated temperatures. Subsequently, a suitable leaving group such as, a halogen, e.g. chloro, can be introduced in the thus formed alcohol derivative using art-known techniques, for instance, reacting the alcohol with thionylchloride in a solvent such as chloroform. 
Some of the compounds of formula (I) and some of the intermediates in the present invention contain at least one asymmetric carbon atom. Pure stereo chemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers.
Pure stereochemically isomeric forms of the compounds of formula (I) may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically. The pure and mixed stereochemically isomeric forms of the compounds of formula (I) are intended to be embraced within the scope of the present invention.
The compounds of formula (I), the N-oxides, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, block the presynaptic xcex12-receptors on central noradrenergic neurons thus increasing the noradrenaline release. Blocking said receptors will suppress or relieve a variety of symptoms associated with a deficiency of noradrenaline in the central or peripheral nervous system. Therapeutic indications for using the present compounds are depression, cognitive disturbances, Parkinson""s disease, diabetes mellitus, sexual dysfunction and impotence and elevated intraocular pressure.
Blocking xcex12 receptors in the central nervous system has also been shown to enhance the release of serotonine which may add to the therapeutic action in depression (Maura et al., 1992, Naunyn-Schmiedeberg""s Arch. Pharmacol., 345:410-416).
It has also been shown that blocking xcex12 receptors may induce an increase of extracellular DOPAC (3,4-dihydro-phenylacetic acid) which is a metabolite of dopamine and noradrenaline.
In view of the usefulness of the subject compounds in the treatment of diseases associated with a deficiency of noradrenaline in the central nervous system, in particular depression and Parkinson""s disease, the present invention provides a method of treating warm-blooded animals suffering from such diseases, in particular depression and Parkinson""s disease, said method comprising the systemic administration of an therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.
The present compounds are also potentially useful in the treatment of Alzheimer""s disease and dementia as it is known that xcex12-antagonists promote the release of acetylcholine (Tellez et al. 1997, J. Neurochem. 68:778-785).
In general it is contemplated that an effective therapeutic daily amount would be from about 0.01 mg/kg to about 4 mg/kg body weight.
The present invention thus also relates to compounds of formula (I) as defined hereinabove for use as a medicine. Further, the present invention also relates to the use of a compound of formula (I) for the manufacture of a medicament for treating depression or Parkinson""s disease.
Ex vivo as well as in vitro receptor signal-transduction and receptor binding studies can be used to evaluate the xcex12 adrenoceptor antagonism of the present compounds. As indices of central (xcex12-adrenoceptor blockade in vivo, the reversal of the loss of righting reflex observed in rats after intravenous injection of xylazine and inhibition of the tremors induced by reserpine in rats can be used.
The compounds of the present invention also have the ability to rapidly penetrate into the central nervous system.
For administration purposes, the subject compounds may be formulated into various pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of formula (I). To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in addition salt or in free acid or base form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action. Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. Addition salts of (I) due to their increased water solubility over the corresponding free base or free acid form, are obviously more suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.